10 (300.0 g, 0.683 mol) and N-hydroxysuccinimide (78.6 g,
0.683 mol) were added. A solution of DCC (147.0 g, 0.716
mol) in DMF (200 mL) was added slowly at such a rate that
the internal temperature did not rise above 30 °C. After 2 h
TLC (silica gel: EtOAc-AcOH-H2O ) 8:1:1, visualized
by UV light. Rf of 10 ) 0.55) indicated completion of the
reaction. The mixture was cooled to 0 °C and stirred for 1
h. DCU was removed by suction filtration, and the cake was
washed with ice-cold DMF ((250 mL). The filtrate was
cooled to 0 °C, and MeOH (1.8 L) was added, keeping the
temperature below 10 °C. Water (1.8 L) was added slowly
at 10 °C; when turbidity appeared, the addition was stopped
to allow induction of crystallization. After completion of the
addition of H2O, the mixture was cooled to 0 °C and stirred
for 1 h. The product was filtered and washed with ice-cold
MeOH/H2O (1:1, 3 × 200 mL) and dried under vacuum at
25 °C to a constant weight to yield 360.0 g (∼98%, corrected
yield 84% vs a standard that was prepared by recrystalliza-
tion)14 of diester 16. 1H NMR (DMSO-d6, 270 MHz) δ 1.56
(s, 6H), 2.90 (s, 4H), 6.82 (s, 1H), 7.08 (s, 1H), 7.20-7.41
(m, 10H), 7.45 (s, 2H). 13C NMR (DMSO-d6, 68 MHz) δ
23.40, 25.60, 76.96, 82.90, 112.10, 126.29, 127.59, 128.34,
140.23, 140.40, 143.37, 158.26, 169.29, 169.66, 171.30.
2-Amino-4-[(1-carboxy-1-methyl-ethoxyimino)-(2,5-
dioxo-pyrrolidin-1-yloxycarbonyl)-methyl]-thiazol-3-
ium Methanesulfonate (18). Intermediate 18 was prepared
by two methods.
transferred with DMF (2 × 20 mL). The reaction flask was
cooled in a ice/NaCl bath to -5 °C. N-Hydroxysuccinimide
(50.0 g, 0.43 mol) was added, and the mixture was stirred
for 3 min. A solution of DCC (95.0 g, 0.46 mol) in EtOAc
(400 mL) was added dropwise at such a rate that the
temperature did not exceed 5 °C. The addition took ∼1 h,
and external cooling was necessary during this process. After
the mixture stirred for 2 h, Et3N (30.0 g) was added through
the addition funnel over 1 min. The temperature of the
mixture rose to 10 °C. After stirring for 1 min, the
precipitated mixture of DCU and Et3NHCl was filtered, and
the filter cake was washed with a mixture (4:1) of EtOAc
and DMF (200 mL) and EtOAc (100 mL). The filtrate was
cooled to 5 °C, and MeOH (28 mL) was added with agitation.
Methanesulfonic acid (36.0 mL) was added within 5 min.
The reaction was exothermic, and its temperature was kept
below 10 °C. The MSA salt of the OSu-ester (18) crystallized
out. After 10 min EtOAc (300 mL) was added, and the
mixture was stirred at 5 °C for 20 min. The product was
filtered, washed with EtOAc (200 mL), and dried under
vacuum to a constant weight to yield 185.0 g (78.3%),
HPLC14 AP 100, mp ∼140 °C, dec. The compound was
1
stored at 5 °C. H NMR (DMSO-d6, 270 MHz) δ 1.51 (s,
6H), 2.49 (s, 3H), 2.89 (s, 4H), 7.13 (s, 1H), 9.0 (broad band
for (NH3)+ and acidic H. Anal. Calcd for C14H18N4O10S2‚
1.0DMF: C, 37.84; H, 4.67; N, 12.98; S, 11.88. Found: C,
37.63; H, 4.64; N, 13.0; S, 11.9.
Method A: By SelectiVe Deprotection of Benzhydryl Ester
16. Anisole (100 mL) and CH2Cl2 (1.0 L) were charged into
a three-necked flask fitted with a mechanical stirrer, ther-
mometer, and an addition funnel. The solution was cooled
to 0 °C, and MSA (100 mL) was added slowly; the
temperature rose to 5 °C. Diester 16 (200.0 g, 0.448 mol)
was added portionwise, keeping the temperature at 0-3 °C.
After 1 h TLC (silica gel: EtOAc, visualized by UV light.
Rf of 16 ) 0.8) indicated completeness of the reaction.
Methyl ethyl ketone (MEK, 2.0 L) was added at a rate such
that the temperature did not exceed 10 °C. Crystallization
of the product started during the addition of MEK. After
stirring for 2 h the product was filtered and washed with
MEK (4 × 100 mL). (Caution! If the cake was not washed
thoroughly, it darkened during the drying process). The
product was dried under vacuum at 25 °C to a constant
weight to give 146.7 g (84.4%) of salt 18, AP 96.9. The
compound was stored at 5 °C.
Method B: By SelectiVe Silylation of the Diacid 9.
2-Amino-R-[(1-carboxy1-methylethoxy)imino]-4-thiazoleace-
tic acid (9)1e (109.2 g, 0.4 mol) and DMF (500 mL) were
charged into a 1-L flask, and DMF (300 mL) was distilled
on a rotary evaporator (50 °C bath temperature) to remove
water. Trimethylchlorosilane (TMSCl, 70.0 mL, 0.55 mol)
was added in one portion, and the mixture was stirred for
15 min. Excess TMSCl along with DMF (∼50 mL) was
evaporated at 65 °C bath temperature, and the solution was
transferred to a three-necked flask. The residual material was
[2S-[2r,3â-(Z)]]-3[[(2-Amino-4-thiazolyl)[(1-carboxy-
1-methylethoxy)-imino]acetyl]amino]-2-methyl-4-oxo-1-
azetidinesulfonic Acid (Aztreonam 1). Method A: By
Acylation of Zwitterion 22 with ActiVe Amide 15. Triethyl-
amine (3.0 mL, 21.5 mmol) was added to a stirring
suspension of azetidinone 221e (0.901 g, 5.0 mmol) in 30%
aqueous EtOH (9.8 mL) precooled to -6 °C. A clear,
colorless solution was obtained. Active amide 15 (2.44 g,
5.02 mmol) was added portionwise over 1 h. EtOH (0.7 mL)
was used to transfer the residual active amide to the reaction
mixture. The mixture was stirred further at -6 to -3 °C for
2 h. Concentrated HCl (1.75 mL) was added dropwise, and
product started precipitating within 2 min. The mixture was
allowed to stand at -3 to 0 °C for 2.5 h. The product was
filtered, washed with a mixture (1:1) of 95% EtOH and H2O
(2 × 2 mL) and EtOH (2 × 2 mL), and dried under vacuum
1
to give 2.38 g (yield ∼81%) of aztreonam 1. H NMR
(DMSO-d6, 270 MHz) δ 1.42 (d, 3H, J ) 5.9 Hz), 1.49 (s,
6H), 3.72 (ddd, 1H, J ) 2.3, 5.9 and 8.2 Hz), 4.49 (dd, 1H,
J ) 2.35 and 7.6 Hz), 4.4-6.1 (broad band for NH3 and
OH), 6.96 (s, 1H), 9.32 (d, 1H, J ) 8.2 Hz). Typical AP of
the aztreonam made by this method was ∼98. The spectral
data of this product was consistent with the reported15 data.
Method B: Telescoped Process from Azetidinone 211e and
ActiVe OSu-ester 18). A mixture (1:1) of MeOH and H2O
(1.4 L) was charged into a 2-L, three-necked flask equipped
with a mechanical stirrer, gas inlet tube, and a pH electrode.
Azetidinone 21 (150.0 g, 0.445 mol) was added, and the
(14) HPLC method: Column: identical to that in ref 13. Solvent: 0.01 M TBA-
HSO4/CH3CN ) 68:32; flow rate 2.0 mL/min; run time 8 min; sample
0.25 mg/mL anhydrous CH3CN; UV detection at 236 nm; Rt diacid 9 )
1.94 min, 17 ) 3.53 min.
(15) (a) Florey, K., Ed. Aztreonam. In Analytical Profiles of Drug Substances;
Academic Press: New York, 1988; Vol 17, pp 1-40 and references therein.
(b) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances, 3rd ed.; Theime Stuttgart: New York, 1999; pp 154-156.
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